1. Field of the Invention
The present invention relates to transcription factors, which induce the transcription of genes. More specifically, the present invention relates to a method of inhibiting transcription factors for use in the therapeutic treatment of disease associated with hyper-activated signal transduction pathways, particularly malignancy.
2. Description of Related Art
Transcription factors bind to specific DNA sequences, usually upstream from the coding region of a gene and affect the transcription of that particular gene. Signal transducers and activators of transcription (STAT) proteins comprise one family of transcription factors. Both for laboratory studies and for potential clinical use, interference with the function of specific transcription factors is a potentially powerful and highly selective way of inhibiting the activation of specific genes and of blocking cellular responses (e.g., cell proliferation, apoptosis, differentiation, activation).
The use of oligonucleotides as therapeutic agents may be able to interact specifically with individual or small numbers of target molecules to inhibit expression of disease-causing genes. For a review see Gewirtz et al (1998 Blood 92:712-736). Most of the attention has been placed on antisense oligonucleotides, DNA triplex-forming oligonucleotides, and ribozymes that are engineered to bind to specific DNA or RNA sequences and inhibit transcription or translation of the target gene. Generally examples of methods for inhibiting transcription factors that have been proposed include the following.
Small molecule pharmacologic agents might be utilized which interrupt signaling or metabolic pathways thus leading to activation of transcription factors. These agents have the disadvantage of non-specifically inhibiting other cellular molecules and functions and having nonspecific toxic effects on cells.
Also, anti-sense oligonucleotides can be used. These molecules often have non-specific effects on the target DNA or RNA which are unrelated to their intended anti-sense inhibition of translation of mRNA. Significant inhibitory effects often are seen even with the control sense oligonucleotides.
A third method involves dominant-negative mutant transfections. This includes the transfection of cDNA encoding non-functional mutants of specific transcription factors or proteins that interact with the transcription factors; such mutants are non-functional, and also interfere with the function of the normal endogenous transcription factor within the cells. These have the disadvantage of the technical difficulty of performing the transfections, isolating the cells that actually are expressing the dominant-negative protein, and regulating the level of expression of the dominant-negative protein in the cells.
It would therefore be useful to have a method for inhibiting transcription factors that does not have these disadvantages and can be used for both in vitro and in vivo use.